Critical Role of the Central 139-Loop in Stability and Binding Selectivity of Arrestin-1

Vishnivetskiy, Sergey A.; Baameur, Faiza; Findley, Kristen; Gurevich, Vsevolod V.

doi:10.1074/jbc.m113.450031

Cited by 58 publications

(64 citation statements)

References 74 publications

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“…The activating conformational rearrangements observed in the crystal structure of p44 include a breaking of the polar core, an increase in interdomain flexibility, and a 21 rotation of the domains relative to one another (Kim et al 2013). In addition, several key loops in the "central crest" region of arrestin, which have been observed experimentally to undergo conformational changes upon receptor binding (Hanson et al 2006;Sommer et al 2007;Kim et al 2012;Vishnivetskiy et al 2013), show significant displacements in p44 as compared to basal arrestin-1. Notably, strikingly similar conformational changes were observed in the crystal structure of nonvisual arrestin-2 (also called β-arrestin-1) in complex with a fully phosphorylated peptide derived from the V2 vasopressin receptor (Shukla et al 2013).…”

Section: Arrestin Structure and Functionmentioning

confidence: 93%

Not Just Signal Shutoff: The Protective Role of Arrestin-1 in Rod Cells

Sommer

Hofmann

Heck

2013

Arrestins - Pharmacology and Therapeutic Potential

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The retinal rod cell is an exquisitely sensitive single-photon detector that primarily functions in dim light (e.g., moonlight). However, rod cells must routinely survive light intensities more than a billion times greater (e.g., bright daylight). One serious challenge to rod cell survival in daylight is the massive amount of all-trans-retinal that is released by Meta II, the light-activated form of the photoreceptor rhodopsin. All-trans-retinal is toxic, and its condensation products have been implicated in disease. Our recent work has developed the concept that rod arrestin (arrestin-1), which terminates Meta II signaling, has an additional role in protecting rod cells from the consequences of bright light by limiting free all-trans-retinal. In this chapter we will elaborate upon the molecular mechanisms by which arrestin-1 serves as both a single-photon response quencher as well as an instrument of rod cell survival in bright light. This discussion will take place within the framework of three distinct functional modules of vision: signal transduction, the retinoid cycle, and protein translocation.

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Section: Arrestin Structure and Functionmentioning

confidence: 93%

Not Just Signal Shutoff: The Protective Role of Arrestin-1 in Rod Cells

Sommer

Hofmann

Heck

2013

Arrestins - Pharmacology and Therapeutic Potential

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“…In arrestin-1, this loop has been designated as the 139-loop and well investigated by several studies (25,31,68). The 139-loop of arrestin-1 is located in the center of the receptor binding surface, next to several elements directly engaged by PR*.…”

Section: Discussionmentioning

confidence: 99%

Identification of Receptor Binding-induced Conformational Changes in Non-visual Arrestins

Zhuo

Vishnivetskiy

Zhan

et al. 2014

Journal of Biological Chemistry

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Background: Non-visual arrestins regulate the signaling of hundreds of GPCRs. Results: Receptor binding-induced conformational changes in non-visual arrestins partially overlap with those in visual arrestin-1. Conclusion: Some receptor binding-induced conformational changes are conserved between arrestin-1, -2, and -3. Significance: Characterization of receptor-induced conformational changes will help identify how the non-visual arrestins interact with hundreds of receptors.

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“…1) with alanines (3A mutation) was found to be a more potent activating mutation that elimination of the positive charge of Arg-382 or its equivalent in nonvisual arrestins (Gurevich 1998; Kovoor et al 1999b; Celver et al 2002a). Interestingly, the deletion of the C-tail beyond its point of contact with the β-strand I and α-helix I yields essentially the same level of phosphorylation-independent binding as its detachment by alanine substitution in all arrestins (Gurevich et al 1997; Gurevich 1998; Celver et al 2002a; Vishnivetskiy et al 2013a, b, c). …”

Section: Construction Of Enhanced Phosphorylation-independent Arresmentioning

confidence: 99%

Enhanced Phosphorylation-Independent Arrestins and Gene Therapy

Gurevich

Song

Vishnivetskiy

et al. 2013

Handbook of Experimental Pharmacology

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A variety of heritable and acquired disorders is associated with excessive signaling by mutant or overstimulated GPCRs. Since any conceivable treatment of diseases caused by gain-of-function mutations requires gene transfer, one possible approach is functional compensation. Several structurally distinct forms of enhanced arrestins that bind phosphorylated and even non-phosphorylated active GPCRs with much higher affinity than parental wild-type proteins have the ability to dampen the signaling by hyperactive GPCR, pushing the balance closer to normal. In vivo this approach was so far tested only in rod photoreceptors deficient in rhodopsin phosphorylation, where enhanced arrestin improved the morphology and light sensitivity of rods, prolonged their survival, and accelerated photoresponse recovery. Considering that rods harbor the fastest, as well as the most demanding and sensitive GPCR-driven signaling cascade, even partial success of functional compensation of defect in rhodopsin phosphorylation by enhanced arrestin demonstrates the feasibility of this strategy and its therapeutic potential.

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Critical Role of the Central 139-Loop in Stability and Binding Selectivity of Arrestin-1

Cited by 58 publications

References 74 publications

Not Just Signal Shutoff: The Protective Role of Arrestin-1 in Rod Cells

Not Just Signal Shutoff: The Protective Role of Arrestin-1 in Rod Cells

Identification of Receptor Binding-induced Conformational Changes in Non-visual Arrestins

Enhanced Phosphorylation-Independent Arrestins and Gene Therapy

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